Jump to content

Myostatin

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Westsomething (talk | contribs) at 08:55, 25 October 2009 (additional photo and little info). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Template:PBB

Myostatin (formerly known as growth differentiation factor 8) is a secreted TGF beta protein family member that inhibits muscle differentiation and growth, i.e. higher concentrations of myostatin in the body cause the individual to have less developed muscles. Myostatin is produced primarily in skeletal muscle cells, circulates in the blood and acts on muscle tissue, by binding a cell-bound receptor called the Activin type II receptor.

Myostatin has been found in humans and several other mammals, as well as in birds and fish. Its functions in non-mammalian vertebrates appear to be somewhat conserved, as muscle-specific actions have been demonstrated in birds. However, it is produced in many different fish tissues, suggesting that it may regulate more than just muscle mass in these vertebrates.

Discovery and sequencing

File:Miostatin1.jpg
"Belgian Blue"

During the last decades looking for ways to restore and increase muscle mass were not only using low molecular weight anabolic and anti-catabolic agents, as well as biologically active food supplements, but also at the level of searching for genes responsible for the homeostasis of muscle tissue. Object to detect such genes were, in particular, and breed of beef cattle with the phenotype of so-called "double-muscle mass (Breed "Belgian Blue" and Piedmontese). Turning in this quest began in 1997.

File:Miostatin2.jpg
"Mighty mouse"

Myostatin and the associated gene were discovered in 1997 by geneticists Alexandra McPherron, Se-Jin Lee and Ravi Kambadur, who also produced a strain of mutant mice that lack the gene and thereby have approximately twice as much muscle as normal mice.[1] These mice were subsequently named "mighty mice".

After that opening in the same 1997 in several laboratories cloned and have established sequence of a gene myostatin at a horned cattle of breeds «Belgian blue» and Piedmontese. It was revealed that these animals have mutations in a gene myostatin (various in each of breeds) which in one way or another lead to absence functionally active myostatin (McPherron A., Lee S-J., 1997; Grobet L. et al., 1997; Kambadur R. et al., 1997). Unlike mice to the damaged gene myostatin at these breeds occurs only hyperplasia a muscular fabric without a hypertrophy. Though with reference to this meat cattle use the term "a phenotype of the doubled muscular weight", the total increase in all muscles makes no more than 40 % in comparison with other meat breeds, but also it, is unconditional, invaluable to meat animal industries. The photo of "Belgian Blue" shows, how absence functionally active myostatin (the gene myostatin works, but the synthesized fiber is inactive) leads to increase in muscular weight.


The gene has been sequenced in humans, mice, several other mammals and many fish species. The primary coding sequence is highly conserved among all vertebrates [2] as is the genomic organization [3]. These and other recent studies also indicate that the myostatin gene in fish has been duplicated as most fish species possess two distinct myostatin genes (MSTN-1 & -2) while salmonids have four (MSTN-1a, -1b, -2a & -2b) [4][5][6] This further suggests that the physiological and developmental aspects of myostatin biology may be quite different from that in mammals.

Effects of inactivated myostatin in cattle

Ravi Kambadur and his team found in 1997 that the double muscled cattle breeds Belgian Blue and Piedmontese have defective myostatin genes; these strains have been produced through breeding. [7][8][9].

The double-muscle mutation in humans

In 2004, a German boy was diagnosed with a mutation in both copies of the myostatin-producing gene, making him considerably stronger than his peers. His mother, a former sprinter, has a mutation in one copy of the gene.[10][11][12][13][14][15]

An American boy born in 2005 was diagnosed with a clinically similar condition but with a somewhat different cause.[16] In contrast to the first case, this boy produces a functional myostatin, however he has a defect in his myostatin receptor so that his muscles do not respond to the myostatin signal.

Performance enhancement in dogs

A "bully whippet" with a homozygous mutation in myostatin. Image from[17]

A 2007 NIH study in PLOS Genetics[17] found a significant relationship in whippets between a myostatin mutation and racing performance. Whippets that were heterozygous for a 2 base pair deletion in myostatin were significantly over-represented in the top racing classes. The mutation resulted in a truncated myostatin mRNA, likely resulting in an inactive form of myostatin.

Whippets with a homozygous deletion were apparently less able runners although their overall appearance was significantly more muscular. Whippets with the homozygous deletion also had an unusual body shape, with a broader head, pronounced overbite, shorter legs, and thicker tails. These whippets have also been called "bully whippets" by the breeding community due to their size, but not their temperament.

This particular mutation was not found in other muscular dog breeds such as boxers and mastiffs, nor was it found in other sighthounds such as greyhounds, Italian greyhounds, or Afghan hounds. The authors of the study suggest that myostatin mutation may not be desirable in greyhounds, the whippets' nearest relative, because greyhound racing requires more significant endurance due to the longer races (900 meters for greyhounds vs. 300 meters for whippets).

Biochemistry

Myostatin is a member of the TGF beta superfamily of proteins.

Human myostatin consists of two identical subunits, each consisting of 109 amino acid residues. Its total molecular weight is 25.0 kDa. It can be produced in genetically engineered E. coli or eukaryotic cells and the recombinant protein from both sources is commercially available. However, due to the unique manner by which the mature protein is processed, there is considerable doubt as to the effectiveness of myostatin generated in E. coli.

Clinical significance

Further research into myostatin and the myostatin gene may lead to therapies for muscular dystrophy.[18] The idea is to introduce substances that block myostatin. In 2002, researchers at the University of Pennsylvania showed that monoclonal antibody specific to myostatin improves the condition of mice with muscular dystrophy, presumably by blocking myostatin's action.

In 2005, Lee showed that a two-week treatment of normal mice with soluble activin type IIB receptor, a molecule that is normally attached to cells and binds to myostatin, leads to a significantly increased muscle mass (up to 60%).[19] It is thought that binding of myostatin to the soluble activin receptor prevents it from interacting with the cell-bound receptors.

It remains unclear whether long term treatment of muscular dystrophy with myostatin inhibitors is beneficial: the depletion of muscle stem cells could worsen the disease later on.

As of 2009, no myostatin-inhibiting drugs for humans are on the market, but an antibody genetically engineered to neutralize myostatin was developed by New Jersey pharmaceutical company Wyeth.[20] The inhibitor is called MYO-029, but after an initial clinical trial, Wyeth says they won't be developing the drug.[21] Some athletes, eager to get their hands on such drugs, turn to the internet, where fake "myostatin blockers" are being sold.[18]

Johns Hopkins University has developed a technique for detecting mutations in myostatin variants.[22]

In fiction

See also

References

  1. ^ McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 1997;387:83-90. PMID 9139826.
  2. ^ Rodgers and Weber. "Sequence conservation among fish myostatin orthologues and the characterization of two additional cDNA clones from Morone saxatilis and Morone americana." Comp Biochem Physiol B Biochem Mol Biol 2001;129(2-3):597-603. PMID 11399495.
  3. ^ Garikipati DK, Gahr SA, Roalson EH, Rodgers BD. "Characterization of rainbow trout myostatin-2 genes (rtMSTN-2a and -2b): genomic organization, differential expression, and pseudogenization." Endocrinology 2007;148(5):2106-15. PMID 17289851.
  4. ^ Kerr T, Roalson EH, Rodgers BD. "Phylogenetic analysis of the myostatin gene sub-family and the differential expression of a novel member in zebrafish." Evol Dev 2005;7(5):390-400. PMID 16174033.
  5. ^ Rodgers BD, Roalson EH, Weber GM, Roberts SB, Goetz FW. "A proposed nomenclature consensus for the myostatin gene family." Am J Physiol Endocrinol Metab 2007;292(2):E371-2. PMID 17003236.
  6. ^ Garikipati DK, Gahr SA, Rodgers BD. "Identification, characterization, and quantitative expression analysis of rainbow trout myostatin-1a and myostatin-1b genes." J Endocrinol 2006;190(3):879-88. PMID 17003288.
  7. ^ Photos of double muscled Myostatin inhibited Belgian Blue Bulls
  8. ^ Kambadur R, Sharma M, Smith T, Bass J (1997). "Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle". Genome Res. 7 (9): 910–6. PMID 9314496.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ McPherron A, Lee S (1997). "Double muscling in cattle due to mutations in the myostatin gene". Proc Natl Acad Sci USA. 94 (23): 12457–61. doi:10.1073/pnas.94.23.12457. PMID 9356471.
  10. ^ cevgenetica: Gene Mutation Makes German Boy Extra Strong Muscle Baby
  11. ^ Gina Kolota: A Very Muscular Baby Offers Hope Against Diseases, The New York Times, June 24, 2004. (Requires login)
  12. ^ Genetic mutation turns tot into superboy
  13. ^ Muscle Boy
  14. ^ One Strong Tyke: Gene mutation in muscular boy may hold disease clues
  15. ^ Schuelke M, Wagner K, Stolz L, Hübner C, Riebel T, Kömen W, Braun T, Tobin J, Lee S (2004). "Myostatin mutation associated with gross muscle hypertrophy in a child". N Engl J Med. 350 (26): 2682–8. doi:10.1056/NEJMoa040933. PMID 15215484.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ Associated Press (2007-05-30). "CTV.ca | Rare condition gives toddler super strength". CTVglobemedia. Retrieved 2009-01-21. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  17. ^ a b Mosher DS, Quignon P, Bustamante CD, Sutter NB, Mellersh CS, et al. A Mutation in the Myostatin Gene Increases Muscle Mass and Enhances Racing Performance in Heterozygote Dogs. PLOS Genetics 2007;PLoS Genetics, e79.eor doi:10.1371/journal.pgen.0030079.eor.
  18. ^ a b Kate Ruder: Strong Boy Could Benefit Research on Muscular Dystrophy, Genome News Network, June 24, 2004.
  19. ^ Lee SJ et al. Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc Natl Acad Sci U S A. Dec 5, 2005. PMID 16330774
  20. ^ 2/23/05 Wyeth MYO-029 press release
  21. ^ 3/11/2008 Wyeth Won't Develop MYO-029 for MD
  22. ^ Methods for detection of mutations in myostatin variants

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Myostatin&oldid=321908138"